C A S E R E P O R T
Open Access
Hydrocortisone malabsorption due to
polyethylene glycols (Macrogol 3350) in a girl
with congenital adrenal insufficiency
Stefano Stagi
*, Paolo Del Greco, Franco Ricci, Chiara Iurato, Giovanni Poggi, Salvatore Seminara
and Maurizio de Martino
Abstract
Background: Primary adrenal insufficiency is relatively rare in children and, if unrecognized, may present with cardiovascular collapse, making it a potentially life-threatening entity.
Case presentation: The proposita, 11 months old of age, was admitted for lethargy and severe dehydration. Blood pressure was 62/38 mm Hg, and biochemical measurements showed hyponatraemia, hypochloraemia, hyperkalaemia, and metabolic acidaemia. Renin activity was 1484μU/mL; cortisol, 1.03 μg/dL (normal, 5-25 μg/dL); and corticotropin (ACTH), 4832 ng/L (normal, 9-52 ng/L). Adrenal deficiency was diagnosed, and replacement therapy with glucocorticoids and mineralocorticoids was initiated. After 40 days, ACTH was 797 ng/L.
During follow-up, the patient started taking macrogol twice daily for constipation and experienced a significant increase in ACTH (3262 ng/L), which dropped to 648 ng/L when macrogol was stopped. After arbitrary reintroduction of macrogol, the child presented with hypoglycaemia, lethargy, weakness, and hypotonia; ACTH was 3145 ng/L. After again stopping macrogol, her ACTH was near normalized (323 ng/L).
Conclusion: Hydrocortisone malabsorption may be caused by macrogol use. Because chronic constipation is frequently reported in children, the possibility that macrogol contributes to adrenal crisis should be taken in account. Keywords: Macrogol, Hydrocortisone, Adrenal insufficiency, Malabsorption, Polyethylene glycol, Constipation Introduction
Adrenal insufficiency is relatively rare in children and may be categorized as primary or secondary and congenital or acquired [1]. Primary adrenal insufficiency can be caused by a deficiency in steroid biosynthesis or abnormal adrenal gland development. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease resulting in impairment of the hypothalamic-pituitary axis. Prompt diagnosis and urgent mineralocortic-oid and glucocorticmineralocortic-oid replacement is mandatory [2]; however, correct management is also essential [3].
Chronic idiopathic constipation is frequently reported and reduces patient quality of life [4,5]. In fact, chronic constipation is associated with long-term problems in-cluding megarectum, reduced sensitivity of the rectum
to the presence of faeces, and abnormal gut motility [4]. In many children, constipation is triggered by painful bowel movements caused by factors such as toilet train-ing, changes in routine or diet, stressful events, intercur-rent illness, or delaying defecation [4]. Therefore, managing chronic constipation in children effectively and early in its course is important in preventing long-term defecation disorders [4].
Polyethylene glycols (PEGs, or macrogols) are hydro-philic polymers of ethylene oxide [6] used in many drugs such as bowel preparations, dispersing agents, and ex-cipients, and in cosmetics [7]. Water makes up 75-80% (wt/wt) of the normal stool, and a difference of only 10% in hydration results in marked changes in stool consistency [8]. Because PEG is a large molecular weight water-soluble polymer, it has the capacity to form hydrogen bonds with 100 molecules of water per molecule of PEG [9]. When PEG is administered orally, the resulting hydration of the * Correspondence:[email protected]
Department of Health Sciences, University of Florence, Anna Meyer Children’s University Hospital, Florence, Italy
© 2014 Stagi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
colonic content facilitates transit and painless defecation in a linear dose-dependent fashion [10]. Therefore, PEG-based laxatives, when used in escalating doses, can also be used to completely remove faecal loading in preference to rectally-administered treatments. Standard management of chronic constipation tends to begin with correction of diet-ary and lifestyle factors that predispose to the condition and focus on increasing dietary fibre and fluid intake [11]. Dietary manipulation alone, including the use of corn syrup, was successful in resolving all symptoms of consti-pation in 25% of children aged up to 2 years in one US study [5].
We describe a girl with adrenal insufficiency managed with hydrocortisone and fluorocortisone who showed an adrenal crisis after administration of macrogol 3350, and we discuss this aspect, focusing on the aetiology of ad-renal insufficiency in childhood.
Case report
The proposita, 11 months old of age, was admitted to Anna Meyer Children’s University Hospital for lethargy and severe dehydration without history of vomiting or diarrhoea. She was the first child of non-consanguineous, young, healthy Italian parents, born at term (39 wks of gestation) by natural childbirth. Birth weight was 3200 g (0.12 standard deviation score [SDS], 50th-75th centile), length, 51 cm (1.12 SDS, 75th-90thcentile), and head cir-cumference, 35 cm (1.04 SDS, 75th-90th centile). There were no perinatal problems or familial history of similar presentations or features of endocrine disease. Neuromo-tor development was normal; she was sitting at 5 months.
At 10 months, 20 days of age, she started showing weight loss, lethargy, weakness, hypotonia, and dark skin. She was mildly dehydrated. Her body weight, length, and head circumference were 10.850 kg (1.89 SDS, 97th cen-tile), 73 cm (0.61 SDS, 50th-75th centile), and 46.5 cm (1.30 SDS, 90thcentile), respectively. There were no dys-morphic features. External genitalia were normal female type with no ambiguity. There was no abdominal or in-guinal mass discovered upon abdominal examination. Blood pressure was 62/38 mm Hg; respiration, 35/min; pulse, 121/min; and body temperature, 37.3°C.
Biochemical measurements indicated hyponatraemia (Na, 125 mEq/L), hypochloraemia (Cl, 86 mEq/L), hyper-kalaemia (K, 5.7 mEq/L), metabolic acidaemia by arterial venous blood gas, elevated serum urea nitrogen (60 mg/dL), and normal creatinine (0.3 mg/dL). Glucose was 56 mg/dL (normal, 55-110 mg/dL). An extensive endocrine work-up, carried out at 8 AM after an overnight fast, showed free thyroxin was 1.27 ng/dL (normal, 0.80-1.90 ng/dL); thyrotropin, 3.96μIU/dL (normal, 0.4-4.0 μIU/dL); aldoster-one, 0.19 nmol/L (normal, 0.96-8.31 nmol/L); renin activity,
1484μU/mL per h (normal, 2-10.2 μU/mL per h);
17-OH-progesterone, < 0.5 nmol/L; dehydroepiandrosterone
sulfate, < 15μg/dL; cortisol, 1.03 μg/dL (normal, 5-25 μg/ dL); ACTH, 4832 ng/L (normal, 9-52 ng/L; Figure 1), luteinizing hormone, 2.3 IU/L; and follicle stimulating hor-mone, 5.6 IU/L.
Serum cortisol and plasma ACTH levels were measured routinely using an Immulite 2000 chemiluminescence immunometric assay (Diagnostic Products Corporation, xLos Angeles, CA, USA). The cortisol inter-assay and intra-assay coefficients of variation were < 9.5% and 7.4%, respectively. The ACTH inter-assay and intra-assay coeffi-cients of variation ranged from 6.1% to 10.0% and from 6.7% to 9.5%, respectively.
The patient was hydrated with normal saline and re-quired vasopressors. Adrenal deficiency was diagnosed considering the hyponatraemia, hyperkalaemia, meta-bolic acidaemia, and cortisol and corticotropin levels.
The usual causes of primary adrenal insufficiency were ruled out (Table 1). Family history was negative for auto-immune diseases and endocrinological or genetic syn-dromes. Renal Doppler ultrasonography was performed and was normal. Autoimmune Addison, in the context of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or other autoimmune syndromes was ruled out by clinical and biochemical evaluation. Mantoux was negative and Veneral Disease Research Laboratory (VDRL) was non-reactive. Human immuno-deficiency virus was seronegative. Plasma levels of very long chain fatty acids (VLCFAs) were normal. We per-formed a synthetic ACTH stimulation test intravenously at 8 AM after an overnight fast, and the cortisol response, measured at 0, 30, and 60 minutes after infusion was blunted (0.98, 1.39, and 2.01μg/dL, respectively). An MRI scan of the bilateral adrenal glands revealed agenesis of the right and hypoplasia of the left adrenal glands (Figures 1A and B).
Replacement therapy with standard doses of gluco-corticoid (hydrocortisone, 15 mg/m2/day), mineralocortic-oid (fluorocortisone, 0.2 mg/day), and sodium chloride (NaCl, 1 g/day) was initiated.
Routine cytogenetic investigations revealed an appar-ently normal female karyotype (46, XX). Molecular karyo-typing was performed using an array comparative genomic hybridization analysis using proband's DNA and a 44 K array platform (Agilent Technologies) with a resolution of approximately 100 kilobase. This examination yielded nor-mal results.
After replacement therapy, electrolyte abnormalities were corrected during the first week, and the patient was discharged in good clinical condition. During follow-up, she maintained good condition, good appetite, weight gain, and normal laboratory results with reduced ACTH (Figure 2). After 10 days, ACTH was 3214 ng/L; renin
ac-tivity, 165.3 μU/mL; Na, 139 mEq/L; K, 4.4 mEq/L; and
At 14 months of age, the patient started taking macro-gol twice daily for constipation, about 30 to 60 minutes after taking hydrocortisone and fluorocortisone. Testing revealed that ACTH was 300 ng/L, and renin activity was
24.2 μU/mL. Analysis of the SF1 gene was normal with
the exception of a c.437G > C polymorphism.
After 3 months of macrogol therapy, Na was 135 mEq/L; Cl, 106 mEq/L; K, 5.3 mEq/L; renin activity, 124.2μU/mL; aldosterone, 0.13 nmol/L; cortisol, 1.78μg/dL; and ACTH, 3262 ng/L. The macrogol was stopped, resulting in a rapid reduction of corticotropin; after 28 days it was 648 ng/L. At this time, faecal elastase was 548 μg/g (normal, > 200μg/g), and steatocrit was 0% (normal, < 3%). Screening for celiac disease was negative (IgA, 38 mg/dL; tTG, 1.0 U/mL).
Unfortunately, the family arbitrarily reintroduced macro-gol (once daily, more than 2 hours after taking hydrocorti-sone and fluorocortihydrocorti-sone) for chronic constipation. After 1 month, during a respiratory tract infection, the child presented with hypoglycaemia, lethargy, weakness, and hypotonia. Vitals were measured: pulse, 134/min; blood pressure, 65/42 mm Hg; and respiration, 38/min. Glucose was 36 mg/dL; Na, 132 nEq/L; Cl, 92 mEq/L; K, 5.4 mEq/L; and ACTH, 3145 ng/L. During recovery, we treated the adrenal deficiency and stopped the macrogol with near normalization of corticotropin (323 ng/L) after 23 days (Figure 2). Neuro-metabolic tests (plasma aminoacidogram,
urine aminoacidogram, acylcarnitine profile analysis, and redox state) were again normal.
Discussion
A variety of laxatives are available for treating constipation: bulk forming, osmotic, and stimulant laxatives. Osmotic laxatives, particularly PEG preparations, are popular be-cause they are relatively safe, inexpensive, and better than lactulose in improving stool frequency and consistency [12-14]. Hydrocortisone is a hydrophilic drug used to treat many conditions, such as primary or secondary adrenal in-sufficiency, hypopituitarism, and adrenogenital syndrome.
Nevertheless, treatment of children suffering from ad-renal insufficiency is frequently problematic for a number of reasons. For example, it requires use of pharmaceutical formulations that do not fully address the pharmacoki-netic and pharmacodynamic problems of dosing infants. Therefore, children require careful monitoring of dose and dosage regimen. In fact, patients with adrenal insuffi-ciency continue to have increased mortality and mor-bidity despite treatment and monitoring [15]. However, many drugs, for example, anticonvulsants such as pheny-toin, phenobarbital, and carbamazepine, stimulate cyto-chrome P450 3A4, induce hepatic enzymes, and lead to accelerated glucocorticoid metabolism and reduced gluco-corticoid effect, possibly causing acute adrenal insuffi-ciency [16].
Table 1 Typical causes of primary adrenal insufficiency
1) Genetic disorders OMIM1 (gene map)
Etiologic mechanisms Other signs and symptoms
Adrenoleukodystrophy 300100 (Xq28) Mutations of ABCD12, ABCD23 Weakness, diminished visual acuity, deafness,
cerebellar ataxia, hemiplegia, convulsions, dementia Congenital adrenal
hyperplasia
21-hydroxylase deficiency 201910 (6p21.33) Mutations of CYP21A24 Hyperandrogenism, ambiguous genitalia in females
11β-hydroxylase deficiency
202010 (8q24.3) Mutations of CYP11B15 Hyperandrogenism, hypertension
3β-hydroxysteroid dehydrogenase type 2 deficiency
201810 (1p12) Mutations of HSD3B26 Ambiguous genitalia in boys, postnatal virilisation in girls
17α-hydroxylase deficiency
202110 (10q24.32) Mutations of CYP17A17 Pubertal delay in both sexes, primary amenorrhea, lack of secondary sexual characteristics, hypertension P450 oxidoreductase
deficiency
201750 (7q11.23) Mutations of POR8 Skeletal malformations, especially craniofacial;
severe abnormal genitalia P450 side-chain cleavage
deficiency
613743 (15q24.1) Mutations of CYP11A19 XY sex reversal Congenital lipoid adrenal
hyperplasia
201710 (8p11.23) Mutations of STAR10 XY sex reversal
Smith-Lemli-Opitz syndrome 270400 (11q13.4) Mutations of DHCR711 Mental retardation, craniofacial malformations, growth failure, cholesterol deficiency Adrenal hypoplasia
congenita
X-linked 300200 (Xp21.2) Mutations of NR0B112 Hypogonadotropic hypogonadism in boys (occasionally in carrier females for skewed X-chromosome inactivation) Xp21 deletion syndrome 300679 (Xp21) Deletion of GK13, DMD14,
and NR0B1
Duchenne muscular dystrophy, glycerol kinase deficiency psychomotor retardation
SF1-linked 612965 (9q33.3) Mutations of NR5A115 XY sex reversal
IMAGe syndrome 614732 (11p15.4) Mutations of CDKN1C16 Intrauterine growth retardation, metaphyseal dysplasia, genital abnormalities
Kearns-Sayre syndrome Deletions of mitochondrial DNA Deafness; heart, ocular and cerebral involvement; skeletal muscle myopathy; intestinal disorders; hormonal deficits Wolman disease 278000 (10q23.31) Mutations of LIPA17 Bilateral adrenal calcification, hepatosplenomegaly
Sitosterolaemia Mutations of ABCG518
and ABCG819 Xanthomata, arthritis, premature coronary arterydisease, short stature, gonadal failure
Familial glucocorticoid deficiency or corticotropin insensitivity syndromes
Type 1 202200 (18p11.21) Mutations of MC2R20 Hyperpigmentation, tall stature, typical facial features,
lethargy and muscle weakness with normal blood pressure Type 2 607398 (21q22.11) Mutations of MRAP21 Hyperpigmentation, normal height, hypoglycaemia,
lethargy, and muscle weakness with normal blood pressure Variant of familial
glucocorticoid deficiency
609981 (8q11.21) Mutations of MCM422 Growth failure, increased chromosomal breakage,
natural killer cell deficiency Primary generalised
glucocorticoid resistance
(5q31.3) Mutations of GCCR23 Fatigue, hypoglycaemia, hypertension, hyperandrogenism
Triple A syndrome (Allgrove’s syndrome)
231550 (12q13.13) Mutations of AAAS24 Achalasia, alacrima, deafness, mental retardation,
hyperkeratosis 2) Acquired diseases Bilateral adrenal haemorrhage - Meningococcal sepsis, antiphospholipid syndrome
Symptoms and signs of underlying disease Bilateral adrenal metastases - Lung, stomach, breast, and
colon cancers
Hydrocortisone preparations are commonly combined with pharmaceutically acceptable carriers, typically inert, to facilitate their administration. Polyethylene glycol con-tains a mixture of inert water-soluble molecules of differ-ent sizes, whose absorption is independdiffer-ent of dosage,
displaying decreasing mucosal transport with increasing molecular size. Macrogol solutions are commonly used for their efficacy and low rate of absorption (0.2%) after oral administration [17] and typically have a safe profile with minimal reported side effects.
Table 1 Typical causes of primary adrenal insufficiency (Continued)
Bilateral adrenalectomy - Adrenal masses, phaeochromocytoma unresolved Cushing’s syndrome
Symptoms and signs of underlying disease Bilateral adrenal infiltration - Adrenal lymphoma, amyloidosis,
haemochromatosis
Disease-associated clinical manifestations Drug-induced adrenal insufficiency - Anticoagulants, ketoconazole, fluconazole, etomidate, phenobarbital, phenytoin, rifampicin, troglitazone
None, unless related to drug
Infectious adrenalitis - Tuberculosis, HIV-1, histoplasmosis, cryptococcosis, coccidioidomycosis, syphilis, trypanosomiasis
Disease-associated manifestations in other organs
Autoimmune adrenalitis
-Isolated None
APS type 1 (APECED) 240300 (21q22.3) Mutations of AIRE25 Chronic mucocutaneous candidosis,
hypoparathyroidism, other autoimmune diseases
APS type 2 269200 Thyroid autoimmune disease, type 1 diabetes,
other autoimmune diseases
APS type 4 Autoimmune gastritis, vitiligo, coeliac disease, alopecia,
excluding thyroid disease and type 1 diabetes
Modified by Charmandari et al., 2014 [16]:1
OMIM: Online Mendelian Inheritance in Man database;2
ABCD1: atp-binding cassette subfamily D, member 1;3 ABCD2: atp-binding cassette, subfamily D, member 2;4
CYP21A2: cytochrome P450, family 21, subfamily A, polypeptide 2;5
CYP11B1: cytochrome P450, subfamily XIB, polypeptide 1; 6
HSD3B2: 3-beta-hydroxysteroid dehydrogenase 2;7
CYP17A1: cytochrome P450, family 17, subfamily A, polypeptide 1;8
POR: cytochrome P450 oxidoreductase;9 CYP11A1: cytochrome P450, subfamily XIA, polypeptide 1;10
STAR: steroidogenic acute regulatory protein;11
DHCR7: 7-dehydrocholesterol reductase;12
NR0B1: nuclear receptor subfamily 0, group B, member 1;13
GK: glycerol kinase;14
DMD: dystrophin;15
NR5A1: nuclear receptor subfamily 5, group A, member 1;16 CDKN1C: cyclin-dependent kinase inhibitor 1C;17
LIPA: lipase A, lysosomal acid;20
MC2R: melanocortin 2 receptor;21
MRAP: melanocortin 2 receptor accessory protein; 22
MCM4: minichromosome maintenance, Saccharomyces Cerevisiae, homolog of, 4;23GCCR: glucocorticoid receptor;24AAAS: AAAS GENE;25AIRE: autoimmune regulator.
Figure 2 Corticotropin (ACTH) serum levels (ng/L) at diagnosis of adrenal insufficiency and the start of hydrocortisone (10 months, 20 days of age), after the start of macrogol (14 and 18 months of age), and after the termination of macrogol (17 and 19 months of age).
A drug’s solubility in water is an important factor in-fluencing its release into the body. In addition, macrogol softens the faecal mass by osmotically drawing water into the GI tract. As our case showed, it is possible that macrogol reduces the absorption of hydrocortisone, fa-cilitating the appearance of adrenal insufficiency. The case seems to support our hypothesis, considering the significant changes in corticotropin after starting and stopping macrogol. Furthermore, we could also specu-late that the introduction of macrogol close to that of hydrocortisone or fluorocortisone could cause or con-tribute to the reduced absorption of these drugs, trigger-ing the adrenal crisis. In fact, it is recognised that many physiological gastrointestinal factors may strongly influence the plasma concentration-time profile of hydrocortisone [18]. However, hydrocortisone has a high permeability in both the small and large intestines, and the short elimin-ation half-life (near 1.5 h) requires two or more dose ad-ministrations per day [18].
This aspect is of great concern because patients with primary or secondary adrenal insufficiency have more than twofold increased mortality than the general popu-lation. However, recent data have demonstrated that the metabolic cardiovascular risk in hypopituitarism is re-lated to the daily dose of hydrocortisone [15].
Our case report, while not demonstrating a genetic
aetiology (polymorphism ofSF1 was the only
abnormal-ity), gives evidence of a possible genetic primary cause of adrenal insufficiency, based on clinical and laboratory examinations and the age of onset. In children, congeni-tal primary adrenal insufficiency is very rare, accounting for about 1% of all cases. The importance of elucidating a genetic basis is emphasised by the ever-increasing number of genetic causes of adrenal insufficiency (Table 1) [16]. In fact, in a series of 103 children with Addison’s dis-ease, genetic forms were very frequent, accounting for 72% of congenital adrenal hyperplasia; other genetic causes accounted for 6%, whereas autoimmune disease was diag-nosed in only 13% [19].
As stressed by this case, prompt diagnosis is also im-portant because acute adrenal insufficiency is a life threat-ening disease. Typically, patients with this disease present with severe hypotension to hypovolaemic shock, vomiting, acute abdominal pain, and often fever. However, children often present with hypoglycaemia and hypoglycaemic seizures. On the other hand, the primary non-specific symptoms of chronic adrenal insufficiency in children are fatigue, reduced muscle strength, weight loss, an-orexia, or failure to thrive [20].
Conclusions
This case report suggests that macrogol 3350 could inter-fere with the absorption of hydrocortisone. It is of particu-lar importance considering the risk of adrenal insufficiency
in these patients, and careful attention should be paid to the concomitant use of macrogol and hydrocorti-sone in subjects with primary or secondary glucocorticoid deficiencies.
Consent
Written informed consent was obtained from the par-ents of the patient for publication of this Case Report and any accompanying images.
Competing interest
The authors declare that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported. Authors’ contributions
SStagi: conception and design, endocrinological evaluation, manuscript writing and final approval of the manuscript. FR: data collection and analysis, manuscript writing and final approval of the manuscript. PDG: data collection and analysis, manuscript writing and final approval of the manuscript. CI: endocrinological evaluation, data collection and analysis, manuscript writing and final approval of the manuscript. GP: data collection and analysis, critical revision and final approval of the manuscript. SSeminara: endocrinological evaluation, critical revision and final approval of the manuscript. MdM: critical revision and final approval of the manuscript. All authors read and approved the final manuscript.
Acknowledgment
We thank Prof. Paolo Lionetti for an invaluable help in revising our manuscript. Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Received: 9 June 2014 Accepted: 4 September 2014 References
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doi:10.1186/s13052-014-0078-2
Cite this article as: Stagi et al.: Hydrocortisone malabsorption due to polyethylene glycols (Macrogol 3350) in a girl with congenital adrenal insufficiency. Italian Journal of Pediatrics 2014 40:78.
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